The pharmacokinetics of cyclosporine. II. Blood plasma distribution and binding studies.

The pharmacokinetic consequences of alterations in the blood plasma distribution of cyclosporine are examined in this study. A series of solutions of cyclosporine of known concentration were prepared in rabbit blood. The plasma, separated at 37 degrees C, was then assayed for cyclosporine using an HPLC method. A mathematical model relating the blood and plasma concentrations of cyclosporine at equilibrium was derived and used to fit the data. The model assumes that the free fraction of the drug in plasma (fp) is constant but that the free fraction in blood is not. In the rabbit, fp was estimated to equal 0.405. This may be attributed to cyclosporine binding to lipoproteins, and to the lower concentrations of lipoproteins in rabbit serum compared to that in human serum. The capacity factor and the binding affinity constant of the drug for blood cells were estimated to equal 3590 micrograms/liter and 0.00682 liter/microgram in the rabbit. These results and the findings of a previous study suggest that the free fraction of the drug in blood increased, while the free intrinsic clearance did not change, with increases in the steady state blood concentration of the drug. It was concluded that the changes in binding characteristics of cyclosporine in blood at higher concentration and not the changes in the metabolic activity of the liver, as measured by intrinsic clearance, are responsible for the nonlinear pharmacokinetic behavior exhibited by cyclosporine in the rabbit.